Download Serotonin

Serotonin
Phase II
Spring 2014
Serotonin
Serotonin (5-hydroxytryptamine, 5-HT)
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An important neurotransmitter,
a local hormone in the gut,
a component of the platelet clotting process,
is thought to play a role in migraine headache
one of the mediators of the signs and symptoms
of carcinoid syndrome, (an unusual manifestation of carcinoid tumor, a
neoplasm of enterochromaffin cells.)
Serotonin
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formed in biologic systems from the amino acid
L-tryptophan
After synthesis, the free amine is stored or is
rapidly inactivated by oxidation catalyzed by the
enzyme monoamine oxidase (MAO).
In the pineal gland, serotonin serves as a
precursor of melatonin, a melanocytestimulating hormone.
In mammals (including humans), over 90% of
the serotonin in the body is found in
enterochromaffin cells in the gastrointestinal
tract.
Serotonin
Cont.
 In the blood, serotonin is found in platelets,
which are able to concentrate the amine by
means of an active serotonin transporter
mechanism (SERT) similar to that in the
membrane of serotonergic nerve endings.
 Once transported into the platelet or nerve
ending, 5-HT is concentrated in vesicles by a
vesicle-associated transporter (VAT) that is
blocked by reserpine.
Serotonin
Cont.
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involved in clinical conditions such as
depression, anxiety, and migraine.
Serotonergic neurons are also found in the
enteric nervous system of the gastrointestinal
tract and around blood vessels.
In rodents (but not in humans), serotonin is
found in mast cells.
Serotonin
Cont.
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Serotonin is also found in the raphe nuclei of
the brainstem, which contain cell bodies of
serotonergic neurons that synthesize, store, and
release serotonin as a transmitter.
Brain serotonergic neurons are involved in
numerous diffuse functions such as mood,
sleep, appetite, and temperature regulation,
as well as the perception of pain, the
regulation of blood pressure, and vomiting.
Serotonin
Serotonin receptor subtypes.
 5-HT1A
 5-HT1B
 5-HT1Da,b
 5-HT1E
 5-HT1F
 5-HT2A
 5-HT2B
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5-HT2C
5-HT3
5-HT4
5-HT5A
5-HT5B
5-HT6
5-HT7
CLINICAL PHARMACOLOGY OF
SEROTONIN
1. Serotonin Agonists
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Serotonin has no clinical applications as a drug.
However, several receptor subtype-selective agonists
have proved to be of value.
Buspirone, a 5-HT1A agonist, has received wide
attention for its usefulness as an effective
nonbenzodiazepine anxiolytic.
Dexfenfluramine, another selective 5-HT agonist, was
widely used as an appetite suppressant but was
withdrawn because of toxicity. Appetite suppression
appears to be associated with agonist action at 5-HT2C
receptors in the central nervous system.
Sumatriptan (5-HT1D/1B agonist) and other triptans
are agonists effective in the treatment of acute migraine
and cluster headache attacks.
Serotonin Agonists
Cisapride, a 5-HT4 agonist, was used in
the treatment of gastroesophageal reflux
and motility disorders. Because of toxicity,
it is now available only for compassionate
use in the USA.
 Tegaserod, a newer 5-HT4 partial
agonist, is used for irritable bowel
syndrome with constipation.
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Serotonin
SEROTONIN-RECEPTOR ANTAGONISTS
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A wide variety of drugs with actions at other receptors (a
adrenoceptors, H1-histamine receptors, etc) are also
serotonin receptor-blocking agents.
Phenoxybenzamine has a long-lasting blocking action
at 5-HT2 receptors.
The ergot alkaloids are partial agonists at serotonin
receptors.
Cyproheptadine has potent H1-receptor-blocking as
well as 5-HT2-blocking actions. The major clinical
applications of cyproheptadine are in the treatment of
carcinoid tumor and in cold-induced urticaria.
Serotonin
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Ketanserin blocks 5-HT1c and 5-HT2 receptors.
However, this drug potently blocks vascular
alpha-1 adrenoceptors. The drug blocks 5-HT2
receptors on platelets and antagonizes platelet
aggregation promoted by serotonin. The
mechanism involved in ketanserin's hypotensive
action is not clear but probably involves alpha-1
adrenoceptors more than 5-HT2 receptor
blockade. Ketanserin is available in Europe for
the treatment of hypertension and vasospastic
conditions but has not been approved in the
USA.
Serotonin
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Ritanserin, another 5-HT2 antagonist, has little
or no alpha-blocking action. It has been reported
to alter bleeding time and to reduce
thromboxane formation, presumably by altering
platelet function.
Ondansetron is the prototypical 5-HT3
antagonist. This drug and its analogs are very
important in the prevention of nausea and
vomiting associated with surgery and cancer
chemotherapy.
THE ERGOT ALKALOIDS
THE ERGOT ALKALOIDS
 Ergot alkaloids are produced by Claviceps
purpurea, a fungus that infects grain under
damp growing or storage conditions.
 This fungus synthesizes histamine,
acetylcholine, tyramine, and other biologically
active products in addition to a score or more of
unique ergot alkaloids.
 These alkaloids affect a adrenoceptors,
dopamine receptors, 5-HT receptors, and
perhaps other receptor types.
 Similar alkaloids are produced by fungi parasitic
to a number of other grass-like plants.
THE ERGOT ALKALOIDS
THE ERGOT ALKALOIDS (cont.)
 The accidental ingestion of ergot alkaloids in
contaminated grain can be traced back more than 2000
years from descriptions of epidemics of ergot poisoning
(ergotism).
 The most dramatic effects of poisoning are dementia
with florid hallucinations; prolonged vasospasm, which
may result in gangrene; and stimulation of uterine
smooth muscle, which in pregnancy may result in
abortion.
 Detailed structure-activity analysis and appropriate
semisynthetic modifications have yielded a large number
of agents with documented or potential clinical value.
THE ERGOT ALKALOIDS
MECHANISM OF ACTION
 the ergot alkaloids act on several types of
receptors.
 Their effects include agonist, partial agonist, and
antagonist actions at alpha-adrenoceptors and
serotonin receptors (especially 5-HT1A and 5HT1D; less for 5-HT1C, 5-HT2, and 5-HT3);
 agonist or partial agonist actions at central
nervous system dopamine receptors.
THE ERGOT ALKALOIDS
Clinical Pharmacology of Ergot Alkaloids
MIGRAINE
Ergot derivatives are highly specific for migraine pain;
 ergotamine is effective when given during the acute
migraine attack; it becomes progressively less effective if
delayed. Ergotamine tartrate is available for oral,
sublingual, rectal suppository, and inhaler use. It is often
combined with caffeine (100 mg caffeine for each 1 mg
ergotamine tartrate) to facilitate absorption of the ergot
alkaloid..
 The vasoconstriction induced by ergotamine is longlasting and cumulative when the drug is taken
repeatedly, as in a severe migraine attack. Therefore,
patients must be carefully informed that no more than 6
mg of the oral preparation may be taken for each attack
and no more than 10 mg per week.
 For very severe attacks, ergotamine tartrate, 0.25-0.5
mg, may be given intravenously or intramuscularly.
THE ERGOT ALKALOIDS
Clinical Pharmacology of Ergot Alkaloids
MIGRAINE(cont)
Dihydroergotamine, 0.5-1 mg
intravenously, is favored by some
clinicians for treatment of persistant
(difficult to manage) migraine. Intranasal
dihydroergotamine may also be effective.
 Methysergide a derivative of ergotamine
may be used in the migraine prophylaxis
THE ERGOT ALKALOIDS
POSTPARTUM HEMORRHAGE
The uterus at term is extremely sensitive to the stimulant
action of ergot, and even moderate doses produce a
prolonged and powerful spasm of the muscle.
 Therefore, ergot derivatives should be used only for
control of late uterine bleeding and should never be
given before delivery.
 Oxytocin is the preferred agent for control of postpartum
hemorrhage, but if this peptide agent is ineffective,
ergonovine maleate, 0.2 mg usually given
intramuscularly, can be tried.
 It is usually effective within 1-5 minutes and is less toxic
than other ergot derivatives for this application.
 It is given at the time of delivery of the placenta or
immediately afterward if bleeding is significant.
THE ERGOT ALKALOIDS
HYPERPROLACTINEMIA
 Increased serum levels of the anterior pituitary
hormone prolactin are associated with secreting
tumors of the gland and also with the use of
centrally acting dopamine antagonists,
especially the D2-blocking antipsychotic drugs.
 Because of negative feedback effects,
hyperprolactinemia is associated with
amenorrhea and infertility in women as well as
galactorrhea in both sexes.
 Bromocriptine is extremely effective in reducing
the high levels of prolactin that result from
pituitary tumors and has even been associated
with regression of the tumor in some cases.
 Cabergoline is similar but more potent.